The activation of central GABA B receptors inhibits the formation of the second messenger, cyclic AMP, by acting through the inhibitory guanine nucleotide (Ni) unit of adenylate cyclase coupling mechanism. We studied the GABA B receptors which are present on cerebellar granule cells in primary culture. Our studies show GABA and baclofen, an analog of GABA, can attenuate basal and forskolin-stimulated adenylate cyclase activity in plasma membranes from these cells and can inhibit the forskolin-stimulated accumulation of cyclic AMP content in intact cerebellar granule cells. This inhibitory action to adenylate cyclase activity and cyclic AMP accumulation can be prevented by pretreating the cerebellar granule cells with a pertusis toxin termed islet activating protein (IAP). IAP reportedly affects the Ni unit so as to prevent the transfer of signal from the activated receptor to the catalytic unit of adenylate cyclase. Presently, we are testing whether this pretreatment with IAP acts by the ADP-ribosylation of the 41,000 dalton subunit of the Ni. Another indicator that the GABA B receptor couples with the Ni unit is that the half maximal concentration of GTP, needed to elicit the baclofen-mediated response to cyclase, is similar to the GTP concentration described for other receptor types coupled to the inhibitory adenylate cyclase. In summary, we have provided more evidence to support our hypothesis that the GABA B receptor directly couples to the Ni unit of adenylate cyclase.